Adding a new layer of complexity to pre-eclampsia

Pre-eclampsia (PE) is a pregnancy complication associated with abnormal formation of the placenta. To date, most studies of PE have focussed on cytotrophoblasts (CTBs) within the villous placenta (the chorion frondosum); the deficient invasion of these cells into the uterine wall is thought to lead to abnormal placentation and hence PE. Here, on p. 767, Susan Fisher and colleagues reveal that CTBs within a different region of the human placenta – the smooth chorion – are implicated in severe PE. They first report that the CTB layer in the smooth chorion is expanded in severe cases of PE and is less organised. These morphological changes are accompanied by changes in the expression profiles of smooth chorion CTBs. In particular, smooth chorion CTBs exhibit enhanced expression of HLA-G, integrin α4 and E-cadherin, all of which are factors that extravillous CTBs normally modulate as they invade the uterine wall. The researchers further show that severe PE is associated with global gene expression changes in smooth chorion CTBs that are distinct from the transcriptional responses of villous and extravillous CTBs to severe PE, which they previously described. Overall, these findings suggest that smooth chorion CTBs play a greater role in placentation and pregnancy outcome than previously appreciated.

Integrins worm their way into brain regeneration

Tissue regeneration involves a number of cellular processes, including proliferation, differentiation, migration and patterning, but it is not clear how all of these processes are coordinated to allow the correct generation and assembly of cells during regeneration. Using the planarian flatworm Schmidtea mediterranea, which displays remarkable regenerative capacity and can regenerate any missing body part, two new studies reveal a key role for integrins in regulating tissue organisation during brain regeneration.

In the first study (p. 784), Nicolle Bonar and Christian Petersen use RNAi to show that β1-integrin regulates cell number and tissue organisation during regeneration following decapitation; in the absence of β1-integrin, brain tissue is disorganised and ectopic cell aggregates form in the head region. By contrast, global patterning is largely unaffected. The authors further show that β1-integrinRNAi animals exhibit an initial delay in regeneration but that this is followed by tissue overproduction. Finally, they report that integrin signalling, likely via a β1/α-2 complex, is required for the proper localisation of neoblasts and progenitor cells during regeneration. Together, these findings suggest that integrin signalling acts to recruit and localise progenitor cells following injury, thereby promoting the correct organisation of regenerating planarian tissue.

In the second paper (p. 795), Florian Seebeck, Kerstin Bartscherer and colleagues demonstrate that β1-integrin RNAi animals, as well as α-integrin-2 RNAi animals, exhibit impaired regeneration following amputation. They show that, in β1-integrin RNAi animals, the newly formed tissues – including the muscle and gut – display structural defects. The researchers also reveal that β1-integrin is required for neoblast migration towards the wound site. Finally, they report that β1-integrin RNAi causes the formation of ectopic neural spheres within the regenerating brain region that are composed of various neuronal cell types and that undergo continuous growth. Overall, these results suggest that integrins are required for the formation of organised tissues and for restricting neurogenesis during planarian regeneration.

Apoptosis: a delayed gut reaction to bacteria

The intestine is a tissue that is known to undergo regeneration, both continuously as part of tissue homeostasis and in response to damage – for example, that induced by bacterial aggression. While many studies have examined how the gut responds to large amounts of pathogenic or opportunistic bacteria, it is unclear how low levels of bacteria might influence gut homeostasis. Here, on p. 808, Armel Gallet and co-workers tackle this issue. They report that small amounts of the opportunistic Gram-positive bacterium Bacillus thuringiensis var. kurstaki induce a mild early stress response mediated by JNK signalling in the Drosophila midgut. This, in turn, induces the proliferation of intestinal stem cells and leads to the accumulation and overcrowding of differentiated intestinal cells (enterocytes). The authors further report that low amounts of ingested bacteria do not trigger apoptosis, whereas larger amounts do. However, they find that a wave of apoptosis is observed days after infection and acts to eliminate the excess enterocytes. Finally, they demonstrate that the Hippo pathway functions cell-autonomously to trigger the removal of supernumerary enterocytes. These findings lead the authors to propose that the mechanisms involved in the response to the ingestion of low amounts of opportunistic bacteria are different to those mediating the ʻregenerative cell deathʼ that occurs following a stronger aggression.

Nucleogenesis gets active

Neurons within the central nervous system can assemble into clusters, termed nuclei, that house neurons with similar synaptic inputs, outputs and function. This process of nucleogenesis, which is crucial for correct circuit formation, is poorly understood. Now, on p. 830, Sarah Guthrie and colleagues show that the correct assembly of developing motor neurons into nuclei in the chick brainstem requires interplay between spontaneous activity, type II cadherins and gap junctions. Using the genetically encoded calcium indicator GCaMP6, they first show that facial motor neurons exhibit activity patterns that change over the course of nucleogenesis. These patterns can be disrupted by perturbing the expression of the type II cadherin Cad20 or the gap junction protein Cx43. The authors further demonstrate that the inhibition of spontaneous activity (using calcium channel inhibitors) results in neuronal disaggregation, and also causes a reduction in the levels of Cad13, another type II cadherin, suggesting the presence of a feedback loop. In summary, these observations suggest that a network of interactions between cadherins, gap junctions and spontaneous activity governs nucleogenesis.

PLUS:

In November 2016, developmental biologists, synthetic biologists and engineers gathered in Paris for a meeting called ‘Engineering the embryo’. The participants shared an interest in exploring how synthetic systems can reveal new principles of embryonic development, and how the in vitro manipulation and modeling of development using stem cells can be used to integrate ideas and expertise from physics, developmental biology and tissue engineering. In their Meeting Review, Anna Kicheva andNicolas Rivron provide a summary of this meeting and highlight the challenges arising at the intersection of these fields.

Krüppel-like factors in mammalian stem cells and development

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that regulate diverse processes such as cell proliferation, differentiation, development and regeneration. Several KLFs are also crucial for maintaining pluripotency and, hence, have been linked to reprogramming and regenerative medicine approaches. In their Primer, Agnieszka Bialkowska, Vincent Yang andSandeep Mallipattu review key functions for KLFs in mammalian embryogenesis, stem cells and regeneration.

Plasticity in the lung: making and breaking cell identity

In recent years, lineage tracing studies have identified distinct epithelial stem and progenitor cell populations in the lung. These cells, together with their differentiated progeny, maintain a stable identity during steady state conditions, but can display remarkable lineage plasticity following injury. In their Review, Purushothama Tata andJayaraj Rajagopal summarize our current understanding of the different cell lineages of the adult mammalian lung and discuss how these populations respond to injury.

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